Gastrointestinal stromal tumors (GISTs) are neoplasms of the soft tissue along the Gl tract. Tumors of this type are prone to metastasize to surrounding tissues or organs. Imatinib mesylate is currently the only therapy with significant success; however, some patients fail to respond to imatinib regimens and others develop resistance over time. Understanding the molecular events mediating GIST metastasis and drug sensitivity will lead to more effective clinical management of GIST. The aims of this study are to identify and functionally characterize genes mediating metastasis and drug response. The proposed research will test two interrelated hypotheses: 1) there are key metastasis-regulating genes that drive GIST invasiveness; and 2) there are key genes that regulate GIST sensitivity to imatinib. A novel three-dimensional cell culture model and high-throughput gene expression studies will be used in combination to screen for candidate genes. High-throughput protein expression profiling and in vitro studies will be used for functional validation. Discovery of these genetic markers will improve the ability to predict the biological behavior of GIST. [unreadable] [unreadable] [unreadable]